An evaluation of the absorption, metabolism, and excretion of orally administered [14C]-TR-701 FA in healthy subjects

Purpose: TR-701 free acid (FA) (tedizolid phosphate) is a novel oxazolidinone prodrug antibiotic currently in phase 3 clinical trials for the treatment of acute bacterial skin and skin structure infections (ABSSSI). Data generated with the oral formulation suggested that 200 mg QD is the lowest effective dose. The aim of the present study was to characterize the absorption, metabolism, and excretion of a single 200-mg dose of [¹⁴C]-TR-701 FA in healthy male subjects to determine its metabolic fate.

Methods: This was an open-label, single-dose study. TR-701 FA was administered orally in 6 healthy male volunteers. Subjects received a single dose of [¹⁴C]-TR-701 FA administered as an oral solution. Blood, urine, and fecal samples were collected at protocol-defined time points. Assays included scintillation counting of blood, plasma, and excreta, a validated LC-MS-MS assay for quantitation of TR-700 (tedizolid) in plasma, and LC-MS and HPLC with radiochemical detection for metabolite profiling.

Results: The majority (87.6%) of the radioactivity was recovered by 96 hours postdose, and total recovery in urine and feces combined was approximately 99.5% by 288 hours postdose. Mean recovery of total radioactivity in urine was 18.0%, with 81.5% of the radioactive dose recovered in feces. Eight metabolites were identified in plasma, urine, and feces. The only significant circulating metabolite found in plasma was the hydrolyzed alcohol product, TR‑700, which constituted approximately 94.54% to 98.23% of sample radioactivity. Other than TR-700, which accounts for approximately 95% of the total radiocarbon AUC in plasma, there are no other significant circulating metabolites. The main metabolite found in feces and urine was the sulfate analog of TR-700. No TR-701 was identified in plasma.

Conclusion: TR-701 underwent rapid and extensive hydrolysis of the phosphate moiety and converted into TR-700, the microbiologically active moiety. Feces were the major elimination pathway. TR-700 was the only appreciable circulating metabolite following oral administration.